This application claims benefit under Title 35, United States Code, xc2xa7119 of European Patent Application No. 01111644.9, filed May 14, 2001.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases reviewed in xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in xe2x80x9cNeuropeptides, 32(1), 1-49, (1998)xe2x80x9d and xe2x80x9cEur. J. Pharmacol., 383(3), 297-303, (1999)xe2x80x9d.
NK1 receptor antagonists have been reported to have also a beneficial effect in the therapy of traumatic brain injury (oral disclosure by Prof. Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, Oct. 17-20, 2000 with the title xe2x80x9cNeurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injuryxe2x80x9d (Authors: A. J. Nimmo, C. J. Bennett, X. Hu, I. Cernak, R. Vink).xe2x80x9d
The present invention relates to compounds of the general formula 
wherein
(R1)n is independently from each other halogen, lower alkyl or lower alkoxy;
R2 is hydrogen, lower alkyl, lower halogen-alkyl, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94NR2, xe2x80x94(CH2)mO-lower alkyl, xe2x80x94(CH2)mxe2x80x94C(O)xe2x80x94NR2, or is xe2x80x94(CH2)m-6-membered heteroaryl, optionally substituted by one or more lower alkoxy, xe2x80x94(CH2)m-5 or 6-membered not aromatic heterocyclyl, optionally substituted by hydroxy or lower alkyl;
R is hydrogen or lower alkyl and may be the same or different in case of R2;
n is 0, 1, or 2;
m is 0, 1, 2, 3 or 4;
and to pharmaceutically acceptable acid addition salts thereof
The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The present invention relates to compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.
The compounds of formula I can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compounds advantages in adsorption, pharmacokinetics in distribution and transport to the brain.
The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term xe2x80x9chalogen-lower alkylxe2x80x9d denotes a lower alkyl group, wherein one or more hydrogen atom(s) is/are replaced by halogen.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9c6-membered heteroarylxe2x80x9d denotes groups, such as triazinyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. Preferred are triazinyl- and pyridinyl groups.
The term xe2x80x9c5 or 6-membered non aromatic heterocyclylxe2x80x9d denotes groups, such as pyrrolidinyl, imidazolidinyl, tetrahydro-pyranyl, piperidyl, piperazinyl or morpholinyl. Preferred are piperazinyl-, morpholinyl-, piperidyl-, tetrahydro-pyranyl- and pyrrolidinyl-groups.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Exemplary preferred are compounds of formula 1, in which R2 is hydrogen, for example the following compounds:
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-5-(3-chloro-phenyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one,
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-5-(3,4-difluoro-phenyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one,
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-5-(3,4-dichloro-phenyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one,
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one,
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-5-(2,3-difluoro-phenyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one and
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-5-(2,5-difluoro-phenyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one.
Further preferred are compounds of formula I, wherein R2 is a xe2x80x94(CH2)m-6-membered heteroaryl group, optionally substituted by one or more lower alkoxy. Examples of such compounds are:
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-5-phenyl-3-pyridin-3-yl-methyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one and
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-3-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one.
Further preferred are compounds of formula I, wherein R2 is xe2x80x94(CH2)mxe2x80x94C(O)xe2x80x94N(CH3)2. An examples of such compounds is:
(5RS)-2-[9-(3,5-bis-trifluoromethyl-benzoyl)-2-oxo-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undec-3-yl]-N,N-dimethyl-acetamide.
Further preferred are compounds of formula I, wherein R2 is xe2x80x94(CH2)mxe2x80x94OH. Examples of such compounds are:
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy-propyl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one and
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one.
Further preferred are compounds of formula I, wherein R2 is a xe2x80x94(CH2)m-5 or 6-membered not aromatic heterocyclyc group, optionally substituted by hydroxy or lower alkyl. Examples of such compounds are:
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-3-(1-methyl-piperidin-4-yl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one,
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-5-phenyl-3-(3-pyrrolidin-1-yl-propyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one,
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-morpholin-4-yl-propyl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one,
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-3-[3-(3-hydroxy-pyrrolidin-1-yl)-propyl]-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one and
(5RS)-9-(3,5-2is-trifluoromethyl-benzoyl)-3-(2-morpholin-4-yl-ethyl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one.
Further preferred are compounds of formula I, wherein R2 is xe2x80x94(CH2)mxe2x80x94NR2. Examples of such compounds are:
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-dimethylamino-4-yl-propyl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one and
(5RS)-9-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-dimethylamino-ethyl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) cyclizing a compound of formula 
xe2x80x83to a compound of formula 
wherein R1 has the significances given above,
or
b) reacting a compound of formula 
xe2x80x83with
R2xe2x80x94X
xe2x80x83to a compound of formula 
xe2x80x83wherein R1 and R2 have the significances given above and X is halogen, or
c) reacting a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83and wherein m and R1 are described above, or
d) reacting a compound of formula 
xe2x80x83with a compound of formula
R2NH
xe2x80x83to a compound of formula 
xe2x80x83wherein the definition for R1 is given above, and R is hydrogen or lower alkyl, or
e) reacting a compound formula 
xe2x80x83to a compound of formula 
xe2x80x83wherein R1 is described above and R2xe2x80x2 and R2xe2x80x3 are independently from each other hydrogen, alkyl, aryl, heteroaryl or taken together a not aromatic carbocyclic or heterocyclic ring, optionally substituted by halogen, hydroxy, lower alkoxy or hydroxy or lower alkyl, and
if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
The following scheme and specific examples 1 to 30 describe the processes for preparation of compounds of formula I in more detail. The starting materials are known compounds and may be prepared according to methods known in the art. 
wherein in this scheme R2xe2x80x2 and R2xe2x80x3 are independently from each other hydrogen, alkyl, aryl, heteroaryl or taken together a not aromatic carbocyclic or heterocyclic ring, optionally substituted by halogen, hydroxy, lower alkoxy, hydroxy or lower alkyl.
In accordance with the scheme above, a compound of formula IV is treated with n-butyllithium in tetrahydrofuran at xe2x88x9278xc2x0 C. for 30 min then a compound V is added and the mixture is stirred at xe2x88x9278xc2x0 C. for 4 hours. The crude product obtained after work-up is hydrogenated in the presence of PtO2 in acetic acid at 2.7 bar. The desired compound of formula II is obtained without purification in moderate to good yields.
A compound of formula II is cyclised to give a compound of formula Ia. The reaction is carried out in a solvent such as tetrahydrofuran in the presence of 1,1xe2x80x2-carbonyl-diimidazole. The reaction mixture is stirred at room temperature for about 18 hours. The desired product was obtained after purification in good yields.
The compound of formula Ia is deprotonated with NaH (sodium hydride 55% in mineral oil) at room temperature in dimethylformamide, dimethoxyethane or N-methylpyrrolidine for 15 min and an alkylating reagent is added. The reaction mixture is stirred at room temperature or at 80xc2x0 C. or at 100xc2x0 C. overnight. The desired compound of formula I is obtained after purification by column chromatography.
A compound of formula I (R2=Me3SiO(CH2)m-1xe2x80x94CH2xe2x80x94) is deprotected under acidic conditions to give a compound of formula Ib without purification.
According to example 23, a compound of formula Ib is treated with methanesulfonyl chloride in dichloromethane at 0xc2x0 C. in presence of triethylamine for 90 min. After work-up, the intermediate methanesulfonate is dissolved in dimethylformamide and sodium hydrogencarbonate and an amine is added. The reaction mixture is stirred overnight at room temperature. The desired product of formula Ic is obtained after purification by column chromatography.
The salt formation is effected at room temperature in accordance with methods which are known.
Example 12, process b) describes the reductive amination reaction of a compound of formula II with a ketone to a compound of formula III. The reaction is carried out in presence of sodium triacetoxyborohydride and acetic acid. The mixture is stirred at room temperature overnight. The desired product is directly used for the next step without purification.
A compound of formula III is cyclised in a solvent such as tetrahydrofuran in presence of 1,1xe2x80x2-carbonyl-diimidazole to give a compound of formula Id. The reaction mixture is stirred at room temperature for about 18 hours. The desired product was obtained after purification in good yields.
The process for preparation of compounds of formula I, described in scheme 1, is novel. The preparation of similar compounds have been described in Eur. J. Med. Chem.xe2x80x94Chim. Ther. (1974), 9(4), 416-23 as follows: 
After debenzylation a reaction with (CF3)2C6H3xe2x80x94C(O)Cl leads to compounds of the present formula I.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids may also be used. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The compounds were investigated in accordance with the tests given hereinafter.
The affinity of test compounds for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (8 xcexcg/ml), MnCl2 (3 mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of [3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The affinity to the NK-1 receptor, given as pKi, is in the scope of 7.50-8.80 for the compounds of formula I of the present invention.
The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used as such excipients e.g. for tablets, dragxc3xa9es and hard gelatine capsules.
Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
The following Examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.